EP2189154A1 - Effervescent tablets and mouth-soluble granulates of S-adenosyl methionine and process for the preparation thereof - Google Patents

Effervescent tablets and mouth-soluble granulates of S-adenosyl methionine and process for the preparation thereof Download PDF

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Publication number
EP2189154A1
EP2189154A1 EP08169848A EP08169848A EP2189154A1 EP 2189154 A1 EP2189154 A1 EP 2189154A1 EP 08169848 A EP08169848 A EP 08169848A EP 08169848 A EP08169848 A EP 08169848A EP 2189154 A1 EP2189154 A1 EP 2189154A1
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same
approximately
batch
composition according
composition
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German (de)
French (fr)
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Davide Bianchi
Marco Berna
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Gnosis SpA
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Gnosis SpA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention refers to effervescent tablets and mouth-soluble granulates of S-adenosyl methionine.
  • SAMe S-Adenosyl methionine
  • This substance is essentially used in clinical practice as an antidepressant.
  • SAMe refers both to the racemic mixture and to the individual diastereoisomers (RS)-(+)-S-adenosyl-L-methionine [(RS)-(+)-SAMe)] and (SS)-(+)-S-adenosyl-L-methionine [(SS)-(+)-SAMe)], as well as to mixtures other than the racemic mixture.
  • S-adenosyl methionine as a drug and/or dietetic is problematic because it is extremely unstable at temperatures above 0°C or in the presence of moisture, resulting either in the degradation of the active ingredient, considered as the sum of the two diastereoisomers, or in the conversion of active (SS)-(+)-S-adenosyl-L-methionine to the inactive (RS)-(+) isomer.
  • Italian Patent 829906 describes a process for the preparation of pharmaceutically acceptable salts of (SS,RS)-S-adenosyl-L-methionine with quantities of the inactive (RS)-(+) diastereoisomer lower than 3%. It is also important to use racemic mixtures with a high percentage of the S,S diastereoisomer which is the only one pharmacologically active. However, the patent confirms that although more than 97% of active S,S diastereoisomer is obtained at ambient temperature, the racemic mixture is unstable over time, with conversion of the (SS)-(+) isomer into the (RS) isomer in a relatively short time.
  • US 354363 , US 136271 and US 354263 disclose a method for stabilising pharmaceutically acceptable salts of S-adenosyl methionine comprising S-adenosyl methionine para-toluene sulphonate, S-adenosyl methionine-1,4-butene disulphonate, S-adenosyl methionine sulphate, S-adenosyl methionine tosylate with a group of substances comprising chitosan, dextran, carboxymethylcellulose, fumaric acid, azelaic acid and tryptophan.
  • US 136271 and US 354363 disclose methods for stabilising S-adenosyl methionine salts using the abovementioned substances in a percentage by weight with respect to the active ingredient which is much higher than 50%, and adding them in reconstituted aqueous solution to S-adenosyl methionine salts, with final lyophilisation. This involves high production costs and very low yields because the % of ions in the final product falls from approximately 50% to approximately 25%.
  • US 3954726 and US 4057672 disclose comparatively stable salts of S-adenosyl methionine, up to 25°C and 45°C, respectively.
  • US 4465672 describes stable salts of S-adenosyl methionine with 5 mols of a sulphonic acid with a pK of less than 2.5, obtained by a process comprising the preparation of a concentrated aqueous solution of an impure salt of SAMe, purification of the solution and its elution with a dilute aqueous solution of the preselected sulphonic acid, titration of the resulting eluate, concentration and lyophilisation or spray-drying. Due to the high instability of SAMe, the use of an aqueous environment is an obvious disadvantage, and even if residual moisture content is successfully contained it is still unacceptable.
  • WO2007/113885 discloses a method for stabilising a solid oral composition of SAMe and/or NADH or their salts, by using calcium oxide or hydroxide optionally in combination with malic acid, glutamic acid, xylitol, calcium sulphate hemihydrate, magnesium oxide and/or mixtures thereof.
  • Effervescent tablets and mouth-soluble granulates are convenient, attractive, easy to use premeasured dosage forms. These advantages, however, also involve some technological problems, the two most important of which are hygroscopicity and lubrication.
  • the granulation has been carried out using very low amounts of water, for example by melting the citric acid monohydrate, which upon heating releases part of the crystallisation water which acts as the granulating fluid.
  • the granulate must be processed in conditions of severely controlled relative humidity, usually lower than 20%.
  • SAMe S-adenosyl methionine
  • the effervescent tablets and mouth-soluble granulates of the invention can be prepared by direct compression in normal thermo-hygrometric conditions and with standard tabletting equipment.
  • calcium oxide is particularly advantageous for the preparation of effervescent tablets and mouth-soluble granulates containing a cyclodextrin as the component of an inclusion complex or as an excipient, notwithstanding the hygroscopic properties of cyclodextrins.
  • SAMe is preferably S-adenosyl methionine para-toluene sulphonate, S-adenosyl methionine-1,4-butene disulphonate, S-adenosyl methionine sulphate, S-adenosyl methionine tosylate, S-adenosyl methionine phytate.
  • the acidic component in the formulations of the invention is selected from citric, tartaric, malic, maleic, fumaric or adipic acid.
  • Anhydrous citric acid and fumaric acid are preferred, in the form of a salt such as mono sodium or potassium fumarate. Fumaric acid allows to decrease the quantity of lubricant.
  • maleic acid optionally present as a salt.
  • mixtures of acids and/or salts are particularly suitable to modulate either the strength of the acid or the lubricant properties.
  • the carbon dioxide source is selected from an alkali or alkaline-earth metal carbonate or bicarbonate or sodium glycine carbonate or mixtures thereof.
  • suitable carbon dioxide sources include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, sodium glycine carbonate.
  • Calcium oxide is mixed with said carbon dioxide sources, particularly carbonates and/or bicarbonates.
  • compositions of the invention may optionally comprise at least one further active ingredient, preferably selected from phosphatidylserine and/or DL-phosphorylserine and/or N-acetyl-L-glutamine and/or L - Carnitine and/or their mixtures.
  • at least one further active ingredient preferably selected from phosphatidylserine and/or DL-phosphorylserine and/or N-acetyl-L-glutamine and/or L - Carnitine and/or their mixtures.
  • the formulation may comprise other excipients such as:
  • Granulated xylitol is particularly preferred as a diluent since it facilitates the blend flowability thereby improving compressibility and machinability.
  • Xylitol, sorbitol, lactose, mannitol, sugar, dextrose, leucine, alanine or mixtures thereof are particularly preferred.
  • Leucine and/or alanine and/or PEG 200 - 8000 are particularly preferred.
  • compositions of the invention contain SAMe or its salts in a quantity from 10 to 95% by weight, preferably from 30 to 90% by weight of the composition.
  • the mixture of calcium oxide/bicarbonate and/or carbonate is generally present in a quantity from 1 to 50% by weight, preferably between 2 and 40% by weight of the composition.
  • the effervescent blend of the invention allows the preparation of highly soluble, stable and small-sized effervescent granulates and mouth-soluble tablets, by direct compressing the components mixture at the standard thermo-hygrometric conditions of normal pharmaceutical production facilities, using standard tabletting machines with normal punches and dies. Also the subsequent processing, storage and packaging can be performed at normal temperature and moisture conditions.
  • the effervescent compositions of the invention solubilize on contact with water and produce a clear solution for oral administration.
  • compositions are the low content of sodium ions, and a less fizzy effervescence, more pleasant to the patient.
  • composition of the invention thanks to its small size, mild effervescence and rapid disintegration, can also be prepared as fast dissolving tablet.
  • the tablet comes in contact with saliva, disintegrates and rapidly forms an easily swallowable solution or aqueous dispersion.
  • compositions according to this invention may be in the form of tablets, capsules, granules and/or powders.
  • the compositions of the invention are in the form of effervescent tablets and mouth-soluble granulates.
  • a further object of this invention is a process for the preparation of effervescent tablets and mouth-soluble granulates comprising SAMe, or their salts, which comprises the following steps:
  • the process is carried out in an environment in which the relative humidity is kept below 20% and the temperature is from 18 to 25°C, preferably about 20°C.
  • Granulation is preferably carried out using a rotating blade granulator fitted with a stainless mesh having holes from 1.2 mm to 3.2 mm in diameter.
  • the active ingredient is preferably mixed with a mixture of calcium oxide/bicarbonate and/or carbonate from approximately 1.0 to approximately 30% by weight and/or fumaric acid from approximately 0.5 to approximately 10% by weight and/or PEG 200 - 8000 from approximately 0.5 to approximately 10% by weight and/or glycine from approximately 0.5 to approximately 2.0% by weight with respect to the active ingredient.
  • the granulate from b) is preferably mixed with malic acid from approximately 1.0 to 10.0% by weight and/or adipic acid from approximately 1.0 to approximately 20.0% by weight and/or leucine from approximately 1.0 to approximately 10% by weight and/or alanine from approximately 1 to approximately 10% by weight of the active ingredient.
  • the optional further active ingredient such as phosphatidylserine, DL-phosphorylserine and/or N-acetyl-L-glutamine and/or L - Carnitine may be added in step c).
  • composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 400.00 mg B. Calcium oxide 20.00 mg C. Anhydrous Calcium chloride 20.00 mg D. Sodium carbonate 75.00 mg E. Anhydrous Citric acid 40.00 mg F. Anhydrous Malic acid 30.00 mg G. Sorbitol 270.00 mg H. Mannitol 119.00 mg I. Sucralose 1.00 mg L. Lemon Flavor 3.00 ng M. Alanine 22.00 mg Total weight of effervescent tablet 1000.00 mg
  • composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 400.00 mg B. Calcium oxide not present 00.00 mg C. Anhydrous Calcium chloride 20.00 mg D. Sodium carbonate 75.00 mg E. Anhydrous Citric acid 40.00 mg F. Anhydrous Malic acid 30.00 mg G. Sorbitol 290.00 mg H. Mannitol 119.00 mg I. Sucralose 1.00 mg L. Lemon Flavor 3.00 ng M. Alanine 22.00 mg Total weight of effervescent tablet 1000.00 mg
  • the working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH.
  • A, B and C were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes.
  • the mixture was transferred to dry containers, always controlling moisture content and temperature.
  • the working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH.
  • D, E, F, G, H, I, and L were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes.
  • the mixture was transferred to dry containers, always controlling moisture content and temperature.
  • the working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH.
  • Mixing A, Mixing B and 50% of M were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes.
  • the resulting mixture was transferred to dry containers, always controlling moisture content and temperature.
  • Precompression of the mixture C was effected using a rotary machine equipped with round punches of 25.0 mm.
  • the hardness of the tablets had to be regulated to subsequently produce a granulate having good flow characteristics.
  • the tablets produced during the first processing stage were granulated on a 1000-1500 ⁇ m mesh, again in a humidity-controlled environment.
  • stage 1.5 The granulate obtained in stage 1.5 was transferred into the mixer, adding 50% of fumaric acid and leaving under stirring for approximately 30 minutes. At the end of this operation the resulting mixture was transferred into dry containers.
  • Final compression of the granulate was carried out using a rotary machine equipped with round punches of 16 mm adjusting the weight to 1100 mg/tablet and the compression force to at least 25 KP.
  • the tablets had a hardness of between 25 and 35 Kp.
  • Friability ⁇ 1.0%; disaggregation time: ⁇ 3 minutes (measured using the method described in U.S.P. 24 th ed.).
  • Table 1 The data in Table 1 show that the tablets have optimum stability.
  • Table 2 Batch 001A - effervescent tablets of 200 mg SAMe ion/tablet (qualitative/quantitative composition in Example 1A) Batch (T/t) 1 Moisture content % (K. Fischer) S,S % AD 2 (%) MTAD 3 (%) SAMe 4 001A (20/0) 0.76 81.7 0.32 0.76 202.23 001AA (60/1) 0.87 50.65 14.56 16.94 136.93 1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine; 4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 401.10 mg B. Calcium oxide 19.80 mg C. Anhydrous Calcium chloride 19.80 mg D. Calcium carbonate 74.89 mg E. Anhydrous Citric acid 37.40 mg F. Anhydrous Malic acid 37.40 mg G. Xylitol 200 264.77 mg H. Anhydrous granular Sorbitol 220.00 mg I. Sucralose 0.88 mg L. Lemon Flavor 2.75 ng M. Furaric acid 22.00 mg Total weight of bags 1100.00 mg
  • composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 401.10 mg B. Calcium oxide (not present) 00.00 mg C. Anhydrous Calcium chloride 19.80 mg D. Anhydrous Calcium carbonate 74.89 mg E. Anhydrous Citric acid 37.40 mg F. Anhydrous Malic acid 37.40 mg G. Xylitol 200 264.77 mg H. Anhydrous granular Sorbitol 239.80 mg I. Sucralose 0.88 mg L. Lemon Flavor 2.75 ng M. Fumaric acid 22.00 mg Total weight of bags 1100.00 mg
  • the working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH.
  • A, B and C were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes.
  • the mixture was transferred to dry containers, always controlling moisture content and temperature.
  • the working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH.
  • D, E, F, G, H, I, and L were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes.
  • the resulting mixture was transferred to dry containers, always controlling moisture content and temperature.
  • the working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH.
  • Mixing A, Mixing B and 100% of M were then transferred to the mixer in the quantities indicated above, leaving them under stirring for approximately 30 minutes. At the end of this operation the mixture was transferred to dry containers, always controlling moisture content and temperature.
  • Precompression of the mixture C was effected using a rotary machine equipped with round punches of 25.0 mm.
  • the hardness of the tablets produced had to be regulated to subsequently produce a granulate having good flow characteristics.
  • the tablets produced during the first processing stage were granulated on a 1000-1500 ⁇ m mesh, again in a humidity-controlled environment.
  • Dissolution time ⁇ minutes (measured using the method described in U.S.P. 28 th ed.)
  • Table 2 show that the tablets have optimum stability.
  • Table 4 Batch 002A - mouth-soluble granulates of 200 mg SAMe ion/bags (qualitative/quantitative composition in Example 2A) Batch (T/t) 1 Moisture content % (K.
  • composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B. Calcium oxide 40.00 mg C. Anhydrous Calcium chloride 40.00 mg D. Sodium bicarbonate 70.00 mg E. Anhydrous Tartaric acid 45.00 mg F. Anhydrous Malic acid 35.00 mg G. Sorbitol 265.00 mg H. Mannitol 119.00 mg I. Aspartame 1.00 mg L. Fruits Flavor 3.00 ng M. Glycine 22.00 mg Total weight of effervescent tablet 1000.00 mg
  • composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B. Calcium oxide not present 00.00 mg C. Anhydrous Calcium chloride 40.00 mg D. Sodium bicarbonate 70.00 mg E. Anhydrous Tartaric acid 45.00 mg F. Anhydrous Malic acid 35.00 mg G. Sorbitol 265.00 mg H. Mannitol 159.00 mg I. Aspartame 1.00 mg L. Fruits Flavor 3.00 ng M. Glycine 22.00 mg Total weight of effervescent tablet 1000.00 mg
  • the quantities relate to the preparation of a standard industrial batch of 300.00 kg of tablets.
  • Table 3 The data in Table 3 show that the tablets have optimum stability.
  • Table 6 Batch 003A - effervescent tablets of 400 mg SAMe ion/tablet (qualitative/quantitative composition in Example 3A) Batch (T/t) 1 Moisture content % (K.Fischer) S,S % AD 2 (%) MTAD 3 (%) SAMe 4 003A (20/0) 0.67 79.56 0.29 0.56 407.23 003AA (60/1) 0.87 49.89 13.58 21.99 298.78 1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine; 4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 802.20 mg B. Calcium oxide 39.60 mg C. Anhydrous Calcium chloride 39.60 mg D. Potassium carbonate 140.00 mg E. Anhydrous Citric acid 74.80 mg F. Anhydrous Adipic acid 84.58 mg G. Dextrose 484.77 mg H. Anhydrous granular Sorbitol 283.19 mg I. Sucralose 1.76 mg L. Lemon Flavor 5.50 ng M. Benzoic acid 44.00 mg Total weight of bags 2000.00 mg
  • the quantities relate to the preparation of a standard industrial batch of 300.00 kg of bags.
  • composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 400.00 mg B. DL Phosphoserine 25.00 mg C. Calcium oxide 20.00 mg D. Anhydrous Calcium chloride 20.00 mg E. Potassium bicarbonate 75.00 mg F. Anhydrous Adipic acid 40.00 mg G. Anhydrous Malic acid 30.00 mg H. Sorbitol 270.00 mg I. Xylitol 144.00 mg L. Sucralose 1.00 mg M. Lemon Flavor 3.00 ng N. Sodium fumarate 22.00 mg Total weight of effervescent tablet 1050.00 mg
  • the quantities relate to the preparation of a standard industrial batch of 300.00 kg of tablets.
  • the tablets were prepared in the manner described in Example 1 using the components and quantities indicated above.
  • composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 401.10 mg B. N-acetyl-L-glutamine 25.00 mg C. Phosphatidylserine 50.00 mg D. Calcium oxide 19.80 mg E. Anhydrous Calcium chloride 19.80 mg F. Sodium carbonate 74.10 mg G. Anhydrous Citric acid 37.40 mg H. Anhydrous Adipic acid 37.40 mg I. Lactose 264.77 mg L. Anhydrous granular Sorbitol 220.00 mg M. Sucralose 0.88 mg N. Lemon Flavor 2.75 ng O. Sodium fumarate 22.00 mg Total weight of bags 1175.00 mg
  • the quantities relate to the preparation of a standard industrial batch of 300.00 kg of bags.
  • the quantities relate to the preparation of a standard industrial batch of 300.00 kg of tablets
  • the tablets were prepared in stoppered glass bottles and enclosed in such a way as to reproduce the conditions of final packaging (generally aluminium/aluminium blister).
  • the samples so prepared were stored for six months in a stove thermostated to a temperature of 40 ⁇ 2°C and 75% RH.
  • Examples 1, 3, 5 Three samples from one batch were used for the 200/400 mg effervescent tablets (Examples 1, 3, 5) and three samples from one batch were used for the mouth-soluble granulates (Examples 2, 4, 6) of 200/400 mg SAMe ion/bags.
  • the tablets were packed in stoppered glass bottles and enclosed so as to reproduce the conditions of final packaging (generally aluminium/aluminium blister).
  • the samples were selected in the same way and in the same quantities as described for the stress test and kept in an environment thermostated to a temperature of 25 ⁇ 2°C and a humidity of 60% RH.
  • Examples 1, 3, 5 Three samples from one batches were used for the 200/400 mg effervescent tablets (Examples 1, 3, 5) and three samples from one batch were used for the mouth-soluble granulates (Examples 2, 4, 6) of 200/400 mg SAMe ion/bags.

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Abstract

A pharmaceutical or nutraceutical composition in form of effervescent tablets or mouth-soluble granulates comprising SAMe, an acid, a carbon dioxide source, calcium oxide and optionally pharmaceutically acceptable excipients.

Description

  • The present invention refers to effervescent tablets and mouth-soluble granulates of S-adenosyl methionine.
    • Background of the invention
  • S-Adenosyl methionine (SAMe) is a physiological donor of methyl groups present in all living organisms, involved in enzyme transmethylation reactions.
  • This substance is essentially used in clinical practice as an antidepressant.
  • "SAMe" refers both to the racemic mixture and to the individual diastereoisomers (RS)-(+)-S-adenosyl-L-methionine [(RS)-(+)-SAMe)] and (SS)-(+)-S-adenosyl-L-methionine [(SS)-(+)-SAMe)], as well as to mixtures other than the racemic mixture.
  • The use of S-adenosyl methionine as a drug and/or dietetic is problematic because it is extremely unstable at temperatures above 0°C or in the presence of moisture, resulting either in the degradation of the active ingredient, considered as the sum of the two diastereoisomers, or in the conversion of active (SS)-(+)-S-adenosyl-L-methionine to the inactive (RS)-(+) isomer.
  • Italian Patent 829906 describes a process for the preparation of pharmaceutically acceptable salts of (SS,RS)-S-adenosyl-L-methionine with quantities of the inactive (RS)-(+) diastereoisomer lower than 3%. It is also important to use racemic mixtures with a high percentage of the S,S diastereoisomer which is the only one pharmacologically active. However, the patent confirms that although more than 97% of active S,S diastereoisomer is obtained at ambient temperature, the racemic mixture is unstable over time, with conversion of the (SS)-(+) isomer into the (RS) isomer in a relatively short time.
  • US 354363 , US 136271 and US 354263 disclose a method for stabilising pharmaceutically acceptable salts of S-adenosyl methionine comprising S-adenosyl methionine para-toluene sulphonate, S-adenosyl methionine-1,4-butene disulphonate, S-adenosyl methionine sulphate, S-adenosyl methionine tosylate with a group of substances comprising chitosan, dextran, carboxymethylcellulose, fumaric acid, azelaic acid and tryptophan. In particular the first of these patents indicates that it is important to have a product with the highest possible amount of S,S diastereoisomer, the R,S diastereoisomer being not only inactive but even opposing the pharmacological effect of the S,S diastereoisomer.
  • US 136271 and US 354363 disclose methods for stabilising S-adenosyl methionine salts using the abovementioned substances in a percentage by weight with respect to the active ingredient which is much higher than 50%, and adding them in reconstituted aqueous solution to S-adenosyl methionine salts, with final lyophilisation. This involves high production costs and very low yields because the % of ions in the final product falls from approximately 50% to approximately 25%.
  • US 3954726 and US 4057672 disclose comparatively stable salts of S-adenosyl methionine, up to 25°C and 45°C, respectively. US 4465672 describes stable salts of S-adenosyl methionine with 5 mols of a sulphonic acid with a pK of less than 2.5, obtained by a process comprising the preparation of a concentrated aqueous solution of an impure salt of SAMe, purification of the solution and its elution with a dilute aqueous solution of the preselected sulphonic acid, titration of the resulting eluate, concentration and lyophilisation or spray-drying. Due to the high instability of SAMe, the use of an aqueous environment is an obvious disadvantage, and even if residual moisture content is successfully contained it is still unacceptable.
  • WO2007/113885 discloses a method for stabilising a solid oral composition of SAMe and/or NADH or their salts, by using calcium oxide or hydroxide optionally in combination with malic acid, glutamic acid, xylitol, calcium sulphate hemihydrate, magnesium oxide and/or mixtures thereof.
  • Effervescent tablets and mouth-soluble granulates are convenient, attractive, easy to use premeasured dosage forms. These advantages, however, also involve some technological problems, the two most important of which are hygroscopicity and lubrication.
  • The instability of effervescent tablets and mouth-soluble granulates, their tendency to absorb moisture and lose reactivity are generally known. Due to this instability in the presence of water, conventional wet granulation and the subsequent granulate compression are hardly applicable.
  • Sometimes the granulation has been carried out using very low amounts of water, for example by melting the citric acid monohydrate, which upon heating releases part of the crystallisation water which acts as the granulating fluid. Thus the granulate must be processed in conditions of severely controlled relative humidity, usually lower than 20%.
  • Alternatively, techniques of dry granulation, in the absence of aqueous phases, have been applied using volatile organic solvents like ethanol. However, such techniques require special manufacturing environments with strictly controlled conditions of relative humidity (normally lower than 20%) and with explosion-proof equipment.
  • Another technique, which is more time-consuming and more laborious, is represented by the separated wet granulation of acidic and alkali granules, which are subsequently mixed and compressed to give the final composition.
  • The direct compression of the simple physical blend of the components of the formulation was proposed to obviate the above difficulties. However such an operation has to be carried out in controlled thermo-hygrometric conditions, for example at temperatures lower than 20-25°C and with relative humidity lower than 20%, using tabletting machines with tapered dies and punches coated with chromium alloys.
  • Other important technological problems affecting the manufacture of effervescent tablets and mouth-soluble granulates concern lubrication, since the lubricant must not only have lipophilic properties for good lubrication, but also high water solubility, to give adequate disintegration and quickly produce a clear solution. Most substances used as lubricants, such as magnesium stearate, although effective, are water insoluble. The resulting solution after disintegration is cloudy and has often a soapy taste. Ideally, non toxic lubricants with high water solubility and acceptable taste are required. Moreover, the effervescent base is inherently difficult to lubricate, partly due to the nature of the raw materials used and partly due to the rapid tablet disintegration usually required which limits the use of high percentages of lubricants.
  • In view of the above mentioned technical problems, it will be appreciated that previous teachings related to non-effervescent oral solid dosage forms are not applicable to effervescent formulations.
    • Description of the invention
  • It has now surprisingly been found that the stable effervescent tablets and mouth-soluble granulates of S-adenosyl methionine (SAMe) may be obtained by mixing calcium oxide with a carbon dioxide source (usually a carbonate or bicarbonate), an acid and optionally other excipients.
  • The effervescent tablets and mouth-soluble granulates of the invention can be prepared by direct compression in normal thermo-hygrometric conditions and with standard tabletting equipment.
  • It has also been found that this technology may be applied also to active ingredients and/or excipients which cannot be wet-granulated or which contain a residual percentage of hardly eliminable crystallisation water.
  • In addition, the use of calcium oxide is particularly advantageous for the preparation of effervescent tablets and mouth-soluble granulates containing a cyclodextrin as the component of an inclusion complex or as an excipient, notwithstanding the hygroscopic properties of cyclodextrins.
  • SAMe is preferably S-adenosyl methionine para-toluene sulphonate, S-adenosyl methionine-1,4-butene disulphonate, S-adenosyl methionine sulphate, S-adenosyl methionine tosylate, S-adenosyl methionine phytate.
  • The acidic component in the formulations of the invention is selected from citric, tartaric, malic, maleic, fumaric or adipic acid. Anhydrous citric acid and fumaric acid are preferred, in the form of a salt such as mono sodium or potassium fumarate. Fumaric acid allows to decrease the quantity of lubricant.
  • Another preferred acid is maleic acid optionally present as a salt. In some cases mixtures of acids and/or salts are particularly suitable to modulate either the strength of the acid or the lubricant properties.
  • The carbon dioxide source is selected from an alkali or alkaline-earth metal carbonate or bicarbonate or sodium glycine carbonate or mixtures thereof. Examples of suitable carbon dioxide sources include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, sodium glycine carbonate.
  • Calcium oxide is mixed with said carbon dioxide sources, particularly carbonates and/or bicarbonates.
  • The compositions of the invention may optionally comprise at least one further active ingredient, preferably selected from phosphatidylserine and/or DL-phosphorylserine and/or N-acetyl-L-glutamine and/or L - Carnitine and/or their mixtures.
  • The formulation may comprise other excipients such as:
    • a lubricant selected from sodium benzoate, sodium and potassium fumarate, leucine, alanine, PEG 200 - 8000;
    • a sweetening agent selected from sucralose, aspartame, saccharin, cyclamate, sugars, preferably sucralose;
    • a diluent selected from lactose, mannitol, xylitol, sorbitol or mixtures thereof and preferably granular xylitol and optionally flavouring agents, ligands, preservatives or others.
  • Granulated xylitol is particularly preferred as a diluent since it facilitates the blend flowability thereby improving compressibility and machinability.
  • Xylitol, sorbitol, lactose, mannitol, sugar, dextrose, leucine, alanine or mixtures thereof are particularly preferred. Leucine and/or alanine and/or PEG 200 - 8000 are particularly preferred.
  • The compositions of the invention contain SAMe or its salts in a quantity from 10 to 95% by weight, preferably from 30 to 90% by weight of the composition.
  • The mixture of calcium oxide/bicarbonate and/or carbonate is generally present in a quantity from 1 to 50% by weight, preferably between 2 and 40% by weight of the composition.
  • The effervescent blend of the invention allows the preparation of highly soluble, stable and small-sized effervescent granulates and mouth-soluble tablets, by direct compressing the components mixture at the standard thermo-hygrometric conditions of normal pharmaceutical production facilities, using standard tabletting machines with normal punches and dies. Also the subsequent processing, storage and packaging can be performed at normal temperature and moisture conditions.
  • The effervescent compositions of the invention solubilize on contact with water and produce a clear solution for oral administration.
  • The possibility to prepare a tablet by direct compression and to obtain a rapid disintegration represents a remarkable formulation improvement.
  • Other advantages of the composition are the low content of sodium ions, and a less fizzy effervescence, more pleasant to the patient.
  • Moreover the composition of the invention, thanks to its small size, mild effervescence and rapid disintegration, can also be prepared as fast dissolving tablet. In fact, when introduced in the mouth, the tablet comes in contact with saliva, disintegrates and rapidly forms an easily swallowable solution or aqueous dispersion.
  • The compositions according to this invention may be in the form of tablets, capsules, granules and/or powders. Preferably, the compositions of the invention are in the form of effervescent tablets and mouth-soluble granulates.
  • A further object of this invention is a process for the preparation of effervescent tablets and mouth-soluble granulates comprising SAMe, or their salts, which comprises the following steps:
    1. a) mixing of the SAMe, or its salts, with a mixture of calcium oxide/bicarbonate and/or carbonate and pharmaceutically acceptable excipients;
    2. b) precompression and subsequent granulation of the mixture from a);
    3. c) mixing of the granulate from b) with an acid selected from malic acid, adipic acid, citric acid, fumaric acid and optionally with pharmaceutically acceptable excipients such as xylitol, sorbitol, lactose, mannitol, sugar, dextrose, leucine, alanine, PEG 200 - 8000 or mixtures thereof;
    4. d) compression of the mixture from c), with the optional addition of sweeteners and/or flavourings.
  • The process is carried out in an environment in which the relative humidity is kept below 20% and the temperature is from 18 to 25°C, preferably about 20°C.
  • Granulation is preferably carried out using a rotating blade granulator fitted with a stainless mesh having holes from 1.2 mm to 3.2 mm in diameter.
  • More particularly, in step a) the active ingredient is preferably mixed with a mixture of calcium oxide/bicarbonate and/or carbonate from approximately 1.0 to approximately 30% by weight and/or fumaric acid from approximately 0.5 to approximately 10% by weight and/or PEG 200 - 8000 from approximately 0.5 to approximately 10% by weight and/or glycine from approximately 0.5 to approximately 2.0% by weight with respect to the active ingredient.
  • In step c), the granulate from b) is preferably mixed with malic acid from approximately 1.0 to 10.0% by weight and/or adipic acid from approximately 1.0 to approximately 20.0% by weight and/or leucine from approximately 1.0 to approximately 10% by weight and/or alanine from approximately 1 to approximately 10% by weight of the active ingredient.
  • The optional further active ingredient such as phosphatidylserine, DL-phosphorylserine and/or N-acetyl-L-glutamine and/or L - Carnitine may be added in step c).
  • The invention is further illustrated in the following examples.
    • EXAMPLE 1
  • Effervescent tablets of 200 mg SAMe ion/tablet
  • Composition based on SAMe sulphate p-toluene sulphonate
    A. SAMe sulphate p-toluene sulphonate 400.00 mg
    B. Calcium oxide 20.00 mg
    C. Anhydrous Calcium chloride 20.00 mg
    D. Sodium carbonate 75.00 mg
    E. Anhydrous Citric acid 40.00 mg
    F. Anhydrous Malic acid 30.00 mg
    G. Sorbitol 270.00 mg
    H. Mannitol 119.00 mg
    I. Sucralose 1.00 mg
    L. Lemon Flavor 3.00 ng
    M. Alanine 22.00 mg
    Total weight of effervescent tablet 1000.00 mg
    • EXAMPLE 1A
  • Effervescent tablets of 200 mg SAMe ion/tablet
  • Composition based on SAMe sulphate p-toluene sulphonate
    A. SAMe sulphate p-toluene sulphonate 400.00 mg
    B. Calcium oxide not present 00.00 mg
    C. Anhydrous Calcium chloride 20.00 mg
    D. Sodium carbonate 75.00 mg
    E. Anhydrous Citric acid 40.00 mg
    F. Anhydrous Malic acid 30.00 mg
    G. Sorbitol 290.00 mg
    H. Mannitol 119.00 mg
    I. Sucralose 1.00 mg
    L. Lemon Flavor 3.00 ng
    M. Alanine 22.00 mg
    Total weight of effervescent tablet 1000.00 mg
    • 1.1. Mixing A
  • The working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH. A, B and C were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes. At the end of this operation the mixture was transferred to dry containers, always controlling moisture content and temperature.
    • 1.2. Mixing B
  • The working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH. D, E, F, G, H, I, and L were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes. At the end of this operation the mixture was transferred to dry containers, always controlling moisture content and temperature.
    • 1.3. Mixing C
  • The working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH. Mixing A, Mixing B and 50% of M were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes. At the end of this operation the resulting mixture was transferred to dry containers, always controlling moisture content and temperature.
    • 1.4. Precompression
  • Precompression of the mixture C was effected using a rotary machine equipped with round punches of 25.0 mm. The hardness of the tablets had to be regulated to subsequently produce a granulate having good flow characteristics.
    • 1.5 Granulation
  • The tablets produced during the first processing stage were granulated on a 1000-1500 µm mesh, again in a humidity-controlled environment.
    • 1.6 Mixing
  • The granulate obtained in stage 1.5 was transferred into the mixer, adding 50% of fumaric acid and leaving under stirring for approximately 30 minutes. At the end of this operation the resulting mixture was transferred into dry containers.
    • 1.7 Compression
  • Final compression of the granulate was carried out using a rotary machine equipped with round punches of 16 mm adjusting the weight to 1100 mg/tablet and the compression force to at least 25 KP. The tablets had a hardness of between 25 and 35 Kp.
  • Friability: ≤ 1.0%; disaggregation time: ≤ 3 minutes (measured using the method described in U.S.P. 24th ed.).
  • Moisture content according to K.F. ≤ 1.00%.
  • Stability tests on effervescent tablets were performed at only 60°C for one month and for a single batch. The samples were stored in alu/alu blister Table 1
    Batch 001 - effervescent tablets of 200 mg SAMe ion/tablet (qualitative/quantitative composition in Example 1)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4
    001 (20/0) 0.54 82.2 0.32 0.45 202.23
    001A (60/1) 0.43 66.32 2.21 4.34 199.43
  • 1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine; 4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • The data in Table 1 show that the tablets have optimum stability. Table 2
    Batch 001A - effervescent tablets of 200 mg SAMe ion/tablet (qualitative/quantitative composition in Example 1A)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4
    001A (20/0) 0.76 81.7 0.32 0.76 202.23
    001AA (60/1) 0.87 50.65 14.56 16.94 136.93
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine; 4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • The data in Table 2 show that the tablets are not stable.
    • EXAMPLE 2
  • Mouth-soluble granulates of 200 mg SAMe ion/bags
  • Composition based on SAMe sulphate p-toluene sulphonate
    A. SAMe sulphate p-toluene sulphonate 401.10 mg
    B. Calcium oxide 19.80 mg
    C. Anhydrous Calcium chloride 19.80 mg
    D. Calcium carbonate 74.89 mg
    E. Anhydrous Citric acid 37.40 mg
    F. Anhydrous Malic acid 37.40 mg
    G. Xylitol 200 264.77 mg
    H. Anhydrous granular Sorbitol 220.00 mg
    I. Sucralose 0.88 mg
    L. Lemon Flavor 2.75 ng
    M. Furaric acid 22.00 mg
    Total weight of bags 1100.00 mg
    • EXAMPLE 2A
  • Mouth-soluble granulates of 200 mg SAMe ion/bags
  • Composition based on SAMe sulphate p-toluene sulphonate
    A. SAMe sulphate p-toluene sulphonate 401.10 mg
    B. Calcium oxide (not present) 00.00 mg
    C. Anhydrous Calcium chloride 19.80 mg
    D. Anhydrous Calcium carbonate 74.89 mg
    E. Anhydrous Citric acid 37.40 mg
    F. Anhydrous Malic acid 37.40 mg
    G. Xylitol 200 264.77 mg
    H. Anhydrous granular Sorbitol 239.80 mg
    I. Sucralose 0.88 mg
    L. Lemon Flavor 2.75 ng
    M. Fumaric acid 22.00 mg
    Total weight of bags 1100.00 mg
    • 1.1. Mixing A
  • The working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH. A, B and C were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes. At the end of this operation the mixture was transferred to dry containers, always controlling moisture content and temperature.
    • 1.2. Mixing B
  • The working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH. D, E, F, G, H, I, and L were then transferred to the mixer in the quantities indicated above, leaving under stirring for approximately 30 minutes. At the end of this operation the resulting mixture was transferred to dry containers, always controlling moisture content and temperature.
    • 1.3. Mixing C
  • The working environment was conditioned to a temperature of 20°C and a relative humidity value of approximately 20% RH. Mixing A, Mixing B and 100% of M were then transferred to the mixer in the quantities indicated above, leaving them under stirring for approximately 30 minutes. At the end of this operation the mixture was transferred to dry containers, always controlling moisture content and temperature.
    • 1.4. Precompression
  • Precompression of the mixture C was effected using a rotary machine equipped with round punches of 25.0 mm. The hardness of the tablets produced had to be regulated to subsequently produce a granulate having good flow characteristics.
    • 1.5 Granulation
  • The tablets produced during the first processing stage were granulated on a 1000-1500 µm mesh, again in a humidity-controlled environment.
  • Dissolution time: ≤ minutes (measured using the method described in U.S.P. 28th ed.)
  • Moisture content according to K.F. ≤ 1.00%
  • Stability tests on effervescent tablets were performed at only 60°C for one months and for a single batch. The samples were stored in alu/alu bags. Table 3
    Batch 002 - mouth-soluble granulates of 200 mg SAMe ion/bags (qualitative/quantitative composition in Example 2)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4
    002 (20/0) 0.57 80.1 0.22 0.32 204.54
    002A (60/1) 0.49 65.52 2.51 5.33 198.76
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine; 4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • The data in Table 2 show that the tablets have optimum stability. Table 4
    Batch 002A - mouth-soluble granulates of 200 mg SAMe ion/bags (qualitative/quantitative composition in Example 2A)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4
    002A (20/0) 0.55 82.4 0.29 0.43 203.74
    002AA (60/1) 0.86 51.72 12.76 18.09 123.98
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine; 4 SAMe sulphate p-toluene sulphonate (mg/bags);
  • The data in Table 2 show that the tablets are not stable.
    • EXAMPLE 3
  • Effervescent tablets of 400 mg SAMe ion/tablet
  • Composition based on SAMe sulphate p-toluene sulphonate
    A. SAMe sulphate p-toluene sulphonate 800.00 mg
    B. Calcium oxide 40.00 mg
    C. Anhydrous Calcium chloride 40.00 mg
    D. Sodium bicarbonate 70.00 mg
    E. Anhydrous Tartaric acid 45.00 mg
    F. Anhydrous Malic acid 35.00 mg
    G. Sorbitol 265.00 mg
    H. Mannitol 119.00 mg
    I. Aspartame 1.00 mg
    L. Fruits Flavor 3.00 ng
    M. Glycine 22.00 mg
    Total weight of effervescent tablet 1000.00 mg
    • EXAMPLE 3A
  • Effervescent tablets of 400 mg SAMe ion/tablet
  • Composition based on SAMe sulphate p-toluene sulphonate
    A. SAMe sulphate p-toluene sulphonate 800.00 mg
    B. Calcium oxide not present 00.00 mg
    C. Anhydrous Calcium chloride 40.00 mg
    D. Sodium bicarbonate 70.00 mg
    E. Anhydrous Tartaric acid 45.00 mg
    F. Anhydrous Malic acid 35.00 mg
    G. Sorbitol 265.00 mg
    H. Mannitol 159.00 mg
    I. Aspartame 1.00 mg
    L. Fruits Flavor 3.00 ng
    M. Glycine 22.00 mg
    Total weight of effervescent tablet 1000.00 mg
  • The quantities relate to the preparation of a standard industrial batch of 300.00 kg of tablets.
  • The tablets were prepared as described in Example 1 using the components and quantities indicated above.
  • Stability tests on effervescent tablets were performed at 60°C for one months and for a single batch. The samples were stored in alu/alu blister. Table 5
    Batch 003 - effervescent tablets of 400 mg SAMe ion/tablet (qualitative/quantitative composition in Example 3)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4
    003 (20/0) 0.65 79.98 0.21 0.35 407.23
    003A (60/1) 0.59 64.30 2.98 5.34 400.01
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • The data in Table 3 show that the tablets have optimum stability. Table 6
    Batch 003A - effervescent tablets of 400 mg SAMe ion/tablet (qualitative/quantitative composition in Example 3A)
    Batch (T/t)1 Moisture content % (K.Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4
    003A (20/0) 0.67 79.56 0.29 0.56 407.23
    003AA (60/1) 0.87 49.89 13.58 21.99 298.78
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • The data in Table 3 show that the tablets have not good stability
    • EXAMPLE 4
  • Mouth-soluble granulates of 400 mg SAMe ion/bags
  • Composition based on SAMe sulphate p-toluene sulphonate
    A. SAMe sulphate p-toluene sulphonate 802.20 mg
    B. Calcium oxide 39.60 mg
    C. Anhydrous Calcium chloride 39.60 mg
    D. Potassium carbonate 140.00 mg
    E. Anhydrous Citric acid 74.80 mg
    F. Anhydrous Adipic acid 84.58 mg
    G. Dextrose 484.77 mg
    H. Anhydrous granular Sorbitol 283.19 mg
    I. Sucralose 1.76 mg
    L. Lemon Flavor 5.50 ng
    M. Benzoic acid 44.00 mg
    Total weight of bags 2000.00 mg
  • The quantities relate to the preparation of a standard industrial batch of 300.00 kg of bags.
  • The tablets were prepared in the manner described in Example 2 using the components and quantities indicated above.
  • Stability tests on effervescent tablets were performed at only 60°C for one months and for a single batch. The samples were stored in alu/alu bags. Table 7
    Batch 004 - mouth-soluble granulates of 400 mg SAMe ion/bags (qualitative/quantitative composition in Example 4)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4
    004 (20/0) 0.74 83.5 0.29 0.13 404.34
    004A (60/1) 0.67 68.45 2.67 5.87 397.74
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/bags);
  • The data in Table 4 show that the tablets have optimum stability
    • EXAMPLE 5
  • Effervescent tablets of 200 mg SAMe ion/tablet
  • Composition based on SAMe sulphate p-toluene sulphonate
    A. SAMe sulphate p-toluene sulphonate 400.00 mg
    B. DL Phosphoserine 25.00 mg
    C. Calcium oxide 20.00 mg
    D. Anhydrous Calcium chloride 20.00 mg
    E. Potassium bicarbonate 75.00 mg
    F. Anhydrous Adipic acid 40.00 mg
    G. Anhydrous Malic acid 30.00 mg
    H. Sorbitol 270.00 mg
    I. Xylitol 144.00 mg
    L. Sucralose 1.00 mg
    M. Lemon Flavor 3.00 ng
    N. Sodium fumarate 22.00 mg
    Total weight of effervescent tablet 1050.00 mg
  • The quantities relate to the preparation of a standard industrial batch of 300.00 kg of tablets.
  • The tablets were prepared in the manner described in Example 1 using the components and quantities indicated above.
  • Stability tests on effervescent tablets were performed at only 60°C for one months and for a single batch. The samples were stored in alu/alu blister. Table 8
    Batch 005 - Effervescent tablets of 200 mg/ion/tablet (qualitative/quantitative composition in Example 5)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 DL-phosphoserine
    005 (20/0) 0.72 81.6 0.29 0.24 211.32 25.54
    005A (60/1) 0.49 75.83 3.62 4.91 200.14 24.83
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • The data in Table 5 show that the tablets have optimum stability.
    • EXAMPLE 6
  • Mouth-soluble granulates of 200 mg SAMe ion/bags
  • Composition based on SAMe sulphate p-toluene sulphonate
    A. SAMe sulphate p-toluene sulphonate 401.10 mg
    B. N-acetyl-L-glutamine 25.00 mg
    C. Phosphatidylserine 50.00 mg
    D. Calcium oxide 19.80 mg
    E. Anhydrous Calcium chloride 19.80 mg
    F. Sodium carbonate 74.10 mg
    G. Anhydrous Citric acid 37.40 mg
    H. Anhydrous Adipic acid 37.40 mg
    I. Lactose 264.77 mg
    L. Anhydrous granular Sorbitol 220.00 mg
    M. Sucralose 0.88 mg
    N. Lemon Flavor 2.75 ng
    O. Sodium fumarate 22.00 mg
    Total weight of bags 1175.00 mg
  • The quantities relate to the preparation of a standard industrial batch of 300.00 kg of bags.
  • The bags were prepared in the manner described in Example 2 using the components and quantities indicated above.
  • Stability tests on effervescent tablets were performed at only 60°C for one month and for a single batch. The samples were stored in alu/alu bags. Table 9
    Batch 006 - Mouth-soluble granulates of 200 mg SAMe ion/bags (qualitative/quantitative composition in Example 6)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTA D3 (%) SAMe 4 N-acetyl-L-glutamine mg Phosphatidylserine mg
    006 (20/0) 0.59 81.11 0.37 0.22 206.89 26.23 53.23
    006A (60/1) 0.53 72.4 0.49 0.59 199.73 25.94 52.24
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine; 4 SAMe sulphate p-toluene sulphonate (mg/bags);
  • The data in Table 6 indicate that the tablets have optimum stability.
  • The quantities relate to the preparation of a standard industrial batch of 300.00 kg of tablets
    • EXPERIMENTAL PART Stability tests on the finished product
  • Stability at 40°C 75% RH (STRESS TEST) and at ambient temperature over a long period (SHELF LIFE) for the compositions of Examples 1, 2, 3, 4, 5, 6 were evaluated for changes in appearance (essentially change in colour), titre of SAMe sulphate p-toluene sulphonate and other active ingredients (mg/tablet; mg/bags), increase in degradation purities, moisture content (K.F.) and % of the active (SS)-(+)-S-adenosyl-L-methionine diastereoisomer; the presence of any degradation products, which can be substantially identified as adenosine and methylthioadenosine, expressed as a percentage with respect to the weight of SAMe-toluene sulphonate per tablet, was further checked by HPLC.
    • STRESS TEST
  • The tablets were prepared in stoppered glass bottles and enclosed in such a way as to reproduce the conditions of final packaging (generally aluminium/aluminium blister).
  • The samples so prepared were stored for six months in a stove thermostated to a temperature of 40 ± 2°C and 75% RH.
  • Three samples from one batch were used for the 200/400 mg effervescent tablets (Examples 1, 3, 5) and three samples from one batch were used for the mouth-soluble granulates (Examples 2, 4, 6) of 200/400 mg SAMe ion/bags.
  • The following tables (10 - 18) report the results of the stress test. Table 10
    Batch 001 - Effervescent tablets of 200 mg SAMe ion/tablet (Example 1)
    Batch (T/t)1 Moisture content % (K.Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    001 (20/0) 0.54 82.2 0.32 0.45 202.23
    001A (40/1) 0.65 75.4 0.36 0.65 201.76
    001B (40/3) 0.53 73.8 0.79 0.74 200.43
    001C (40/6) 0.60 68.0 0.87 1.21 197.54
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine; 4 SAMe sulphate p-toluene sulphonate (mg/tablet);
    Table 11
    Batch 002 - Mouth-soluble granulates of 200 mg SAMe ion/bags (Example 2)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    002 (20/0) 0.57 80.1 0.22 0.32 204.54
    002A (40/1) 0.62 76.4 0.54 0.76 203.65
    002B (40/3) 0.77 73.8 0.59 0.82 202.61
    002C (40/6) 0.79 69.6 0.87 0.99 198.01
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine; 4 SAMe sulphate p-toluene sulphonate (mg/bags);
    Table 12
    Batch 003 - Effervescent tablets of 400 mg SAMe ion/tablet (Example 3)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    003 (20/0) 0.65 79.9 0.21 0.35 407.23
    003A (40/1) 0.73 75.8 0.57 0.49 405.98
    003B (40/3) 0.69 73.6 0.79 0.79 404.88
    003C (40/6) 0.76 67.5 1.08 0.98 401.81
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
    Table 13
    Batch 004 - Mouth-soluble granulates of 400 mg SAMe ion/bags (Example 4)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    004 (20/0) 0.74 83.5 0.29 0.13 404.34
    004A (40/1) 0.45 75.9 0.59 0.35 402.76
    004B (40/3) 004C (40/6) 0.49 71.7 0.58 0.57 400.61
    0.76 69.9 0.99 0.78 398.94
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/bags);
    Table 14
    Batch 05 - Effervescent tablets of 200 mg SAMe ion/tablet (Example 5)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe 4 mg DL-phosphoserine Mg
    005 (20/0) 0.72 81.6 0.29 0.24 211.32 25.54
    005A (40/1) 0.59 73.3 0.59 0.54 209.75 24.65
    005B (40/3) 0.61 70.8 0.69 0.78 207.56 24.55
    005C (40/6) 0.87 68.9 0.77 1.65 205.65 24.32
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
    Table 15
    Batch 06 - Mouth-soluble granulates of 200 mg SAMe ion/bags (Example 6)
    ot (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD 3 (%) SAMe4 mg N-acetyl-L-glutamine mg Phosphatidylserine mg
    006 (20/0) 0.59 81.1 0.37 0.22 206.89 26.23 53.23
    006A (40/1) 0.55 73.8 0.35 0.59 205.89 25.02 52.02
    006B (40/3) 0.65 70.1 0.64 0.87 203.65 24.98 51.98
    006C (40/6) 074 68.3 0.95 1.17 200.65 24.95 51.45
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/bags);
  • From the stability data at 40°C and 75% RH (STRESS TEST) it is evident that all the batches examined after six months suffered degradation equal to approximately 7.0% of both SAMe and the other active ingredients with a reduction of approximately 13% in the active (SS)-(+)-S-adenosyl-L-methionine diastereoisomer. Table 16
    Batch 001A - Effervescent tablets of 200 mg SAMe ion/tablet (Example 1A)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    001A (20/0) 0.76 81.7 0.32 0.76 202.23
    001AA (40/1) 0.87 55.4 2.36 8.89 178.98
    001AB (40/3) 0.93 51.8 7.65 15.84 154.63
    001AC (40/6) 1.60 49.7 13.65 21.21 121.74
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
    Table 17
    Batch 002A - Mouth-soluble granulates of 200 mg SAMe ion/bags (Example 2A)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    002A (20/0) 0.55 82.4 0.29 0.43 203.74
    002AA (40/1) 0.68 58.4 3.84 7.83 168.05
    002AB (40/3) 0.97 53.7 8.49 17.44 147.72
    002AC (40/6) 1.65 49.9 14.93 22.79 119.61
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/bags);
    Table 18
    Batch 003A - Effervescent tablets of 400 mg SAMe ion/tablet (Example 3A)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    003 (20/0) 0.67 79.5 0.29 0.56 407.23
    003AA (40/1) 0.93 57.5 3.05 6.59 345.67
    003AB (40/3) 1.49 53.6 7.69 15.20 304.85
    003AC (40/6) 1.78 48.5 12.88 20.67 267.89
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • From the stability data at 40°C and 75% RH (STRESS TEST) it is evident that all the batches without calcium oxide after six months suffered degradation equal to approximately 40% of both SAMe and the other active ingredients with a reduction of approximately 30% in the active (SS)-(+)-S-adenosyl-L-methionine diastereoisomer.
    • SHELF LIFE
  • The tablets were packed in stoppered glass bottles and enclosed so as to reproduce the conditions of final packaging (generally aluminium/aluminium blister).
  • The samples were selected in the same way and in the same quantities as described for the stress test and kept in an environment thermostated to a temperature of 25 ± 2°C and a humidity of 60% RH.
  • Three samples from one batches were used for the 200/400 mg effervescent tablets (Examples 1, 3, 5) and three samples from one batch were used for the mouth-soluble granulates (Examples 2, 4, 6) of 200/400 mg SAMe ion/bags.
  • The following tables 19 - 27 show the results for SHELF LIFE. Table 19
    Batch 001 - Effervescent tablets of 200 mg SAMe ion/tablet (Example 1)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    001 (20/0) 0.54 82.2 0.32 0.45 202.23
    001A (25/3) 0.76 77.3 0.49 0.37 202.00
    001B (25/6) 0.58 74.5 0.57 0.55 201.89
    001C (25/12) 0.66 72.9 0.63 0.68 200.76
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
    Table 20
    Batch 002 - Mouth-soluble granulates of 200 mg SAMe ion/bags (Example 2)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    002 (20/0) 0.57 80.1 0.22 0.32 204.54
    002A (25/3) 0.66 76.6 0.36 0.57 203.78
    002B (25/6) 0.59 74.5 0.54 0.65 203.00
    002C (25/12) 0.36 73.4 0.67 0.76 202.54
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/bags);
    Table 21
    Batch 003 - Effervescent tablets of 400 mg SAMe ion/tablet (Example 3)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    003 (20/0) 0.65 79.9 0.21 0.35 407.23
    003A (25/1) 0.45 74.5 0.35 0.55 407.44
    003B (25/6) 0.59 73.6 0.63 0.59 406.32
    003C (25/12) 0.65 72.65 0.76 0.78 405.53
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
    Table 22
    Batch 004 - Mouth-soluble granulates of 400 mg SAMe ion/bags (Example 4)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    004 (20/0) 0.70 80.0 0.41 0.20 410.24
    004A (25/3) 0.64 75.7 0.54 0.47 408.65
    004B (25/6) 0.55 73.7 0.69 0.58 407.56
    004C (25/12) 0.43 74.4 0.83 0.85 406.58
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/bags);
    Table 23
    Batch 05 - Effervescent tablets of 200 mg SAMe ion/tablet (Example 5)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg DL-phosphoserine mg
    005 (20/0) 0.61 80.0 0.52 0.53 410.54 2.03
    005A (25/3) 0.57 75.4 0.55 0.58 409.65 2.03
    005B (25/6) 0.51 74.3 0.67 0.69 408.56 2.00
    005C (25/12) 0.48 73.0 0.76 0.78 407.98 1.95
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
    Table 24
    Batch 06 - Mouth-soluble granulates of 200 mg SAMe ion/bags (Example 6)
    ot (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg N-acetyl-L-glutamine mg Phosphatidylserine mg
    006 (20/0) 0.59 81.1 0.37 0.22 206.89 26.23 53.23
    006A (25/3) 0.65 74.6 0.54 0.47 204.76 25.02 52.02
    006B (25/6) 0.78 73.8 0.49 0.68 204.33 24.92 51.87
    006C (25/12) 0.63 72.6 0.68 0.75 203.77 24.65 51.66
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/bags);
  • From the stability data at 25°C and 60% RH (SHELF LIFE) it is evident that all the batches examined after twelve months suffered very little degradation of the SAMe with a reduction of approximately 10% in the active (SS)-(+)-S-adenosyl-L-methionine diastereoisomer. Table 25
    001A - Effervescent tablets of 200 mg SAMe ion/tablet (Example 1A)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    001A (20/0) 0.76 81.7 0.32 0.76 202.23
    001AA (25/3) 0.78 67.3 1.49 2.03 189.34
    001AB (25/6) 1.68 54.2 5.48 7.99 164.99
    001AC (25/12) 1.86 50.9 10.63 13.49 148.48
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
    Table 26
    Batch 002A - Mouth-soluble granulates of 200 mg SAMe ion/bags (Example 2A)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    002A (20/0) 0.55 82.4 0.29 0.43 203.74
    002AA (25/3) 0.73 68.2 1.39 2.34 187.31
    002AB (25/6) 1.48 56.8 5.00 7.76 168.59
    002AC (25/12) 1.56 51.3 10.01 12.39 150.46
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/bags);
    Table 27
    Batch 003A - Effervescent tablets of 400 mg SAMe ion/tablet (Example 3A)
    Batch (T/t)1 Moisture content % (K. Fischer) S,S % AD2 (%) MTAD3 (%) SAMe4 mg
    003A (20/0) 0.67 79.5 0.29 0.56 407.23
    003AA (25/1) 0.75 64.5 2.35 2.33 389.73
    003AB (25/6) 0.79 53.9 6.62 8.29 356.89
    003AC (25/12) 1.25 49.29 11.22 15.79 308.49
    1 Temperature (°C)/time (months); 2 adenosine; 3 methylthioadenosine;
    4 SAMe sulphate p-toluene sulphonate (mg/tablet);
  • From the stability data at 25°C and 60% RH (SHELF LIFE) it is evident that all the batches without calcium oxide after twelve months suffered very hard degradation of the SAMe with a reduction of approximately 30% in the active (SS)-(+)-S-adenosyl-L-methionine diastereoisomer.

Claims (12)

  1. A pharmaceutical or nutraceutical composition in form of effervescent tablets or mouth-soluble granulates comprising SAMe, an acid, a carbon dioxide source, calcium oxide and optionally pharmaceutically acceptable excipients.
  2. A composition according to Claim 1, in which SAMe is S-adenosyl methionine para-toluene sulphonate, S-adenosyl methionine-1,4-butene disulphonate, S-adenosyl methionine sulphate, S-adenosyl methionine tosylate, S-adenosyl methionine phytate.
  3. A composition according to claim 1 or 2, in which SAMe is present in a quantity from approximately 10 to approximately 95% by weight of the composition.
  4. A composition according to claim 3, in which SAMe is present in a quantity approximately from 30 to 90% by weight of the composition.
  5. A composition according to any one of claims from 1 to 4 wherein the acid is selected from citric, tartaric, malic, maleic, fumaric or adipic acid.
  6. A composition according to any one of claims 1 to 5 wherein the carbon dioxide source is selected from an alkali or alkaline-earth metal carbonate or bicarbonate or sodium glycine carbonate or mixtures thereof.
  7. A composition according to any one of claims 1 to 6, in which the mixture of calcium oxide/bicarbonate and/or carbonate is present in a quantity from approximately 1 to approximately 50% by weight of the composition.
  8. A composition according to claim 7, in which the mixture of calcium oxide/bicarbonate and/or carbonate is present in a quantity from approximately 5 to approximately 30% by weight of the composition.
  9. A composition according to any one of claims 1 to 8, comprising at least one further active ingredient selected from phosphatidylserine, DL-phosphorylserine, N-acetyl-L-glutamine and L - Carnitine.
  10. A composition according to any one of claims 1 to 9 comprising glycine and/or leucine and/or PEG 200 - 8000 as excipients.
  11. A process for the preparation of a tablet of claims 1-10 comprising the following steps:
    a) mixing of the SAMe and/or their salts with a mixture of calcium oxide/bicarbonate and/or carbonate and pharmaceutically acceptable excipients;
    b) precompression and subsequent granulation of the mixture from a);
    c) mixing of the granulate from b) with other excipients;
    d) compression of the mixture from c), with the optional addition of sweeteners and/or flavours.
  12. A process according to Claim 11, in which the absolute moisture content is lower than 40%-50% and the temperature is maintained at 20°C -25°C.
EP08169848A 2008-11-25 2008-11-25 Effervescent tablets and mouth-soluble granulates of S-adenosyl methionine and process for the preparation thereof Withdrawn EP2189154A1 (en)

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WO2010089674A1 (en) * 2009-02-09 2010-08-12 Graal Srl Orosoluble and/or effervescent compositions containing at least a salt of s- adenosyl methionine (same)
EP2857001A4 (en) * 2012-05-28 2015-12-30 Hot Album Tansansen Tablet Inc PROCESS FOR MANUFACTURING TABLET AND TABLET
FR3025104A1 (en) * 2014-08-29 2016-03-04 Hy Nutrition IMMEDIATE RELEASE BOLUS
US9649274B2 (en) 2012-06-12 2017-05-16 The Procter & Gamble Company Effervescent dosage form
GB2545007A (en) * 2015-12-03 2017-06-07 Cosmetic Warriors Ltd Composition
US10617714B2 (en) 2012-06-12 2020-04-14 The Procter & Gamble Company Effervescent dosage form
WO2023228167A3 (en) * 2023-09-04 2024-05-02 Carlo De Angelis Solid food or pharmaceutical formulation, methods for obtaining and drying it and its uses in pharmaceutical, nutraceutical or veterinary products
WO2025133891A1 (en) * 2023-12-19 2025-06-26 Lesaffre Et Compagnie Stable mouth-dissolving formulations based on s-adenosyl methionine

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WO2010089674A1 (en) * 2009-02-09 2010-08-12 Graal Srl Orosoluble and/or effervescent compositions containing at least a salt of s- adenosyl methionine (same)
EP2857001A4 (en) * 2012-05-28 2015-12-30 Hot Album Tansansen Tablet Inc PROCESS FOR MANUFACTURING TABLET AND TABLET
US10322144B2 (en) 2012-06-12 2019-06-18 The Procter & Gamble Company Effervescent dosage form
US9649274B2 (en) 2012-06-12 2017-05-16 The Procter & Gamble Company Effervescent dosage form
US10028977B2 (en) 2012-06-12 2018-07-24 The Procter & Gamble Company Effervescent dosage form
US10617714B2 (en) 2012-06-12 2020-04-14 The Procter & Gamble Company Effervescent dosage form
US9668971B2 (en) 2014-08-29 2017-06-06 Hy-Nutrition Immediate-release bolus
FR3025104A1 (en) * 2014-08-29 2016-03-04 Hy Nutrition IMMEDIATE RELEASE BOLUS
GB2545007A (en) * 2015-12-03 2017-06-07 Cosmetic Warriors Ltd Composition
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US10894004B2 (en) 2015-12-03 2021-01-19 Cosmetic Warriors Limited Composition
WO2023228167A3 (en) * 2023-09-04 2024-05-02 Carlo De Angelis Solid food or pharmaceutical formulation, methods for obtaining and drying it and its uses in pharmaceutical, nutraceutical or veterinary products
WO2025133891A1 (en) * 2023-12-19 2025-06-26 Lesaffre Et Compagnie Stable mouth-dissolving formulations based on s-adenosyl methionine

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